Aging is a fundamental process characterized by progressive declines in physiological functions of multiple tissues (i.e. functional aging) and an increased likelihood of death at later adult ages. Motor activity decline represents one of the most prominent physiological declines in aging animals and humans. In fact, it has been linked to impairments in mobility and physical functioning in the elderly and appears to act as a risk factor for loss of independence and mortality. In humans, the age-related decline in motor activity appears to be the result of decreases in the number and function of both muscle cells and motor neurons. However, the cellular mechanisms underlying the origin of these age-related alterations remain largely unknown. The neuronal contribution of such decline is particularly understudied. The nematode C. elegans has recently emerged as an excellent model system for aging studies because of its short lifespan and amenability to genetic manipulation. Much of the current efforts in aging research carried out in model organisms have been directed at understanding the mechanisms by which genetic and environmental cues influence longevity. However, very little is known about the mechanisms underlying functional aging in C. elegans. The goal of our research is to investigate these mechanisms. C. elegans also exhibits many aging phenotypes that resemble those found in higher organisms, including the age-related decline in motor activity. However, the same question arises as to what mechanisms may underlie the progressive decline in motor activity observed in aging worms. Interestingly, our studies suggested that the progressive decline in the function of motor nervous system might also contribute to the age-related decline in motor activity, which was previously not known in C. elegans. Therefore, in this proposal, we aim to further dissect the role of the motor nervous system in the age-related decline in motor activity. More specifically, using a set of electrophysiological assays, we would like to investigate the cellular mechanisms underlying age-dependent functional decline at the neuromuscular junctions (NMJs) during normal aging. One goal of our research is to ultimately develop new therapeutic strategies that could prevent or delay the age-related declines in mobility and increases in fatigability that often occur in the elderly population. In fact, our preliminary results indicate that pharmacological stimulation of the aging nervous system by a muscarinic acetylcholine receptor (mAChR) agonist as well as genetic manipulations of genes known to slow aging can improve motor function in aged worms. Thus, in the second part of this proposal, we will focus on understanding the physiological and cellular mechanisms by which these pharmacological or genetic interventions improve motor activity in aged animals. PUBLIC HEALTH RELEVANCE: During the normal aging process in humans, decreased motor activity and loss of skeletal muscle strength and mass appears to be inevitable. In fact, motor activity represents one of the most prominent physiological declines in aging animals and humans. However, the mechanisms underlying the age-related declines in motor activity remain unclear. Our previous studies in C. elegans have suggested that the progressive decay in the function of the motor nervous system may, at least in part, contribute to such decline. Therefore, further understanding the role of nervous system in the age-related decline of motor activity could lead to possible interventions that would benefit the frail elderly population.